The preparation and delivery of active agents including small molecules and biologics (e.g., proteins, carbohydrates, nucleic acids, hormones, lipids) in powder or microparticle form is an area of concentrated research and development activity in a variety of applications including pharmaceuticals (where the active agent is an Active Pharmaceutical Ingredient (API)), nutraceuticals and cosmetics. In many cases it is desirable for the microparticles to have a predetermined, relatively uniform size because size can impact the deposition of the microparticles and release of the API.
In the case of inhalable microparticle formulations it is particularly important that microparticle size be controlled so that the API can be delivered to the appropriate region(s) of the respiratory tract. Examples of diseases that can be treated by delivery of a pharmaceutical formulation to the upper and/or central respiratory tract include respiratory tract infections (RTIs) such as influenza, parainfluenza, RSV, sinusitis, otitis, laryngitis, bronchitis and pneumonia. In addition, there are large numbers of respiratory tract disorders (RTDs) that may not be caused by an infectious pathogen but affect the upper and central respiratory tract; such disorders, which can have a genetic basis, arise due to immunodeficiencies or other (e.g., α-1-antitrypsin) deficiencies, result from exposure to allergens and/or chemical pollutants, or present as complications of infectious diseases such as the RTIs described above or inflammatory diseases such as inflammatory bowel syndrome and Crohn's disease include allergic and non-allergic asthma, COPD, bronchiectasis, vasculitis, mucous plugging, Wegener's granulomatosis and cystic fibrosis (CF).
In some cases, for example, when an infection is present in the lower respiratory tract, it can be desirable to administer a formulation containing microparticles that are delivered to the lower and central respiratory tract. Thus, in some cases it can be desirable to administer a formulation containing microparticles that have an MMAD of 3-8 microns or 5-7 microns. The smaller MMAD of the microparticles in such formulations can increase the fraction of microparticles that are small enough to become absorbed into the bloodstream. Since systemic exposure is sometimes not desirable, the formulations with a relatively small MMAD can pose increase risk of unwanted systemic exposure. However, tight control over the range of the particle size can reduce the risk. Moreover, for some patients, e.g., immunocompromised patients, suffering from influenza or parainfluenza, the importance of delivering therapy to the lower respiratory tract justifies a potential increase in risk of a small degree of systemic exposure.
For the treatment of RTIs and RTDs, the microparticles of the drug must be small enough to be deposited and act at the desired target site in the upper and/or central respiratory airways of the lungs (e.g., the epithelial cells of the upper respiratory tract in the case of influenza; the central respiratory tract in the case of asthma or COPD), yet not be so small as to reach deeper parts of the lungs, such as the alveoli, become absorbed into the bloodstream, and compromise the pharmacokinetic profile or even the safety of the drug. Accordingly, there is a need for a method of producing microparticle formulations whose size can be fine-tuned for delivery to a target site of interest while reducing delivery to sites that are undesirable.
There further is a need for microparticle formulations in which the incorporated active agent is stable for relatively long periods of time. For stability, the active agent in the formulation should not react with or otherwise be degraded by other ingredients/excipients in the formulation (for example, compounds that improve bioavailability, delivery, safety, etc. of the active agent). The active agent in the formulation should also be protected from components that may be present in the packaging materials and/or delivery systems, e.g., medical devices, containers, capsules or gels. For example, when the active agent is a protein, aldehydes and other cross-linking agents that may be present in some packaging materials or arise as byproducts during the manufacture of the materials can react with the active agent to form protein aggregates or oligomers. There is a need for microparticle formulations that can protect the active agent against components of packaging materials that could compromise its stability.